Our laboratory is interested in immune activation and, in particular, the molecular mechanisms underlying the activation of T cells, a key step during an immune response. Our initial approach to gain fundamental insights into the early phase of activation of human primary T lymphocytes involved the isolation by subtractive technologies of novel mitogen- and antigen-inducible genes. Characterization of several of the more than 60 genes isolated in this way has led to the discovery of several cytokines, transmembrane proteins, a phosphatase, a ras-related protein and six different transcription _factors. Two of these originally cloned factors are part of the NF-kappaB transcription factor complex called p50 and p50B. NF-kappaB is an important component of the immune response; it is essential to the regulated expression of many immunomodulatory proteins, acute phase proteins and viruses, including the human immunodeficiency virus (HIV). Upon antigen- or cytokine- or stress-mediated signalling NF-kappaB is released from a cytoplasmic inhibitor called I-kappa-B to translocate to the nucleus. We have determined that NF-kappaB activity is created from different homo-and heterodimeric complexes which all differ in their functions. The homodimeric p50 complex actually acts as a repressor in the nucleus opposing the transactivating heterodimeric complexes. Both types of complexes are independently regulated by members of the I-kappa-B family: I-kappa-B inhibits transactivating complexes and the oncoprotein Bcl-3 inhibits the repressing complexes; these inhibitory molecules therefore have opposite effects on gene expression. The complexity of the NF-kappaB transcription factor suggests an equally complex regulatory role during immune activation.